Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke that produces severe neurologic deficits in survivors. Mechanisms of brain injury after intracerebral hemorrhage have been identified during the past decade. Now we know that several processes are responsible for brain injury around the clot. These include coagulation cascade activation with thrombin production, complement cascade activation in the brain parenchyma, and hemoglobin- and iron-induced toxicity. Despite our increased knowledge of ICH-induced injury, there is still no current therapeutic treatment. Estrogen has been shown to be strongly neuroprotective in experimental cerebral ischemia. Our preliminary data show that estrogen reduces brain edema after ICH in mice and in rats. The mechanisms involved in estrogen-induced protection are unknown, a recent study demonstrates that estrogen reduces complement-mediated ischemia-reperfusion injury in heart. Our data lead us to hypothesize that estrogen may also limit complement-mediated brain injury after ICH. To test these hypotheses, we will undertake the following Specific Aims: 1) Determine whether estrogen reduces ICH-induced brain damage; 2) Determine whether estrogen can reduce membrane attack complex formation, erythrocyte lysis and iron overload; 3) Determine whether estrogen attenuates inflammatory response. Our overall goal is to understand the mechanisms of estrogen-induced neuroprotection after ICH. It is important to understand the mechanisms behind the estrogen-induced protective effects since acute use estrogen could be a new therapy for ICH. It is not possible to directly transpose data on estrogen from cerebral ischemia studies since the mechanisms of brain injury in ICH and cerebral ischemia are different. PUBLIC HEALTH RELEVANCE: Estrogen has been shown to confer strong brain protection in experimental cerebral ischemia. We have found that brain edema is reduced when estrogen is given before or after ICH. The mechanisms involved in estrogen-induced protection are unknown. A recent study demonstrates that estrogen reduces complement-mediated ischemia-reperfusion injury in heart. This study will focuses on the effects of estrogen on complement-mediated brain injury after ICH. It is important to determine the mechanisms underlying the protective effects of estrogen in ICH as the mechanisms of ICH-induced injury differ from ischemia. [unreadable] [unreadable] [unreadable]